What is the best treatment approach for a patient with persistent vomiting, considering potential underlying causes such as gastrointestinal infection, food poisoning, or gastroparesis, and taking into account the patient's hydration status, electrolyte levels, and any relevant past medical history, including pregnancy or history of gastrointestinal issues?

Treatment of Persistent Vomiting

For persistent vomiting, initiate dopamine receptor antagonists (metoclopramide 10 mg PO/IV three times daily, prochlorperazine, or haloperidol) as first-line therapy, titrated to maximum benefit and tolerance, while simultaneously addressing hydration status and identifying underlying causes. 1, 2

Initial Assessment and Stabilization

Hydration and Electrolyte Management

• Oral rehydration solution (ORS) is first-line therapy for mild to moderate dehydration in all age groups with vomiting, even when vomiting is present. 3
• Continue ORS administration even if vomiting occurs—wait 10 minutes after an episode, then resume giving fluid more slowly in small sips at short intervals, as most fluid is retained despite apparent vomiting. 3, 4
• Isotonic intravenous fluids (lactated Ringer's or normal saline) should be administered when there is severe dehydration, shock, altered mental status, failure of ORS therapy, or ileus. 3
• Ensure adequate fluid intake of at least 1.5 L/day and correct electrolyte abnormalities, particularly hypokalemia and hypomagnesemia, which commonly occur with prolonged vomiting. 1

Laboratory Evaluation

• Obtain complete blood count, serum electrolytes, glucose, liver function tests, lipase, and urinalysis to exclude metabolic causes and assess dehydration severity. 1
• Consider testing for hypercalcemia, hypothyroidism, and Addison's disease if clinically indicated. 1
• Urine drug screen is warranted to assess for cannabis use, particularly in younger patients where Cannabis Hyperemesis Syndrome should be suspected. 1

Stepwise Pharmacologic Algorithm

First-Line: Dopamine Receptor Antagonists

• Start metoclopramide 10 mg PO/IV three times daily before meals, which is particularly effective for gastric stasis and can be titrated to maximum benefit. 1, 2, 5
• Alternative dopamine antagonists include prochlorperazine or haloperidol 0.5-2 mg PO/IV every 4-6 hours. 1, 6
• Administer antiemetics on a scheduled basis rather than PRN, as prevention is far easier than treating established vomiting. 1
• Monitor for extrapyramidal side effects, particularly in young males and elderly patients; treat with diphenhydramine 50 mg IV if they develop. 1, 5

Second-Line: Add 5-HT3 Antagonist

• If vomiting persists after 4 weeks of dopamine antagonist therapy, add ondansetron 8 mg PO 2-3 times daily or 0.15 mg/kg IV (maximum 16 mg per dose). 1, 2
• Ondansetron acts on different receptors than dopamine antagonists, providing complementary antiemetic coverage. 1
• Consider sublingual formulation to improve absorption in actively vomiting patients. 2
• Monitor for QTc prolongation, especially when combined with other QT-prolonging agents. 1

Third-Line: Combination Therapy

• Combine ondansetron with dexamethasone 10-20 mg IV, as this combination is superior to either agent alone for refractory symptoms. 1
• Use agents from different drug classes simultaneously rather than sequential monotherapy, as no single agent has proven superior for breakthrough emesis. 3, 1
• Multiple concurrent agents in alternating schedules may be necessary for refractory cases. 3, 1

Alternative Routes When Oral Route Fails

• Consider rectal suppositories (promethazine or prochlorperazine), sublingual tablets (ondansetron), or continuous IV/subcutaneous infusion when oral administration is not feasible due to ongoing vomiting. 1, 2

Treatment of Specific Underlying Causes

Gastroparesis or Gastritis

• Continue metoclopramide as it promotes gastric emptying in addition to antiemetic effects. 1, 2
• Add proton pump inhibitor or H2 receptor antagonist for gastritis or gastroesophageal reflux. 1, 2

Metabolic Abnormalities

• Correct hypercalcemia, treat dehydration, and address electrolyte imbalances identified on initial laboratory testing. 1, 2
• In patients with ketonemia, an initial course of intravenous hydration may be needed to enable tolerance of oral rehydration. 3

Cannabis Hyperemesis Syndrome

• Definitive diagnosis requires 6 months of cannabis cessation or at least 3 typical cycle lengths without vomiting. 1
• Do not stigmatize patients with cannabis use—offer abortive and prophylactic therapy even with ongoing use, as treatments can still be effective. 1

Pregnancy-Related Vomiting

• Thiamine (vitamin B1) supplementation is crucial to prevent Wernicke's encephalopathy in patients with persistent vomiting, particularly in pregnancy. 1, 7
• Hyperemesis gravidarum requires hospitalization, intravenous fluid and electrolyte replacement, thiamine supplementation, conventional antiemetics, and psychological support. 7

Refractory Symptoms: Additional Options

• For severe, persistent vomiting unresponsive to combination therapy, consider adding olanzapine 2.5-5 mg PO daily, particularly in palliative care settings. 2, 6
• Dronabinol 2.5-7.5 mg PO every 4 hours as needed is FDA-approved for refractory nausea unresponsive to conventional antiemetics. 3, 1
• Lorazepam 0.5-1 mg PO/IV every 4-6 hours may be added for anxiety-related nausea, but avoid long-term use due to dependence risk. 2, 6
• Consider adding an H2 blocker or proton pump inhibitor if dyspepsia is present, as patients may confuse heartburn with nausea. 3, 1

Critical Pitfalls to Avoid

• Never use antiemetics in suspected mechanical bowel obstruction, as this can mask progressive ileus and gastric distension. 1, 2
• Avoid repeated endoscopy or imaging unless new symptoms develop; one-time upper GI imaging or EGD is sufficient to exclude obstructive lesions. 1
• Do not use antiemetics such as chlorpromazine routinely during gastroenteritis, as they have undesirable side effects and vomiting usually subsides with continued ORT. 4
• Antimotility drugs (loperamide) should not be given to children <18 years of age with acute diarrhea and should be avoided in inflammatory diarrhea or diarrhea with fever at any age. 3
• Ondansetron may increase stool volume/diarrhea in gastroenteritis, which should be considered when selecting antiemetics. 1

Special Population Considerations

Elderly Patients

• Start with reduced doses (25-50% reduction): metoclopramide 5 mg three times daily, haloperidol 0.5 mg, lorazepam 0.25 mg. 6
• Elderly patients are especially sensitive to benzodiazepines and antipsychotics; monitor closely for extrapyramidal side effects and confusion. 6, 5
• Geriatric patients should receive the lowest effective dose, and if parkinsonian-like symptoms develop, discontinue metoclopramide before initiating anti-parkinsonian agents. 5

Pediatric Patients

• Ondansetron 0.2 mg/kg oral (maximum 4 mg) is indicated in children unable to take fluids orally due to persistent vomiting. 8
• Dystonias and extrapyramidal reactions are more common in pediatric populations than adults. 5
• Breastfed infants should continue nursing throughout the illness. 3